Autonomic nerve regulating agent

ABSTRACT

The autonomic-nerve regulating agent of the present-invention, which, has a sedative action, sleep inducing action, and stress mitigating action in individuals, regardless of individual variation in sensitivity to or preference for fragrance, contains as an active ingredient a sesquiterpene alcohol with a boiling point of 250° C. or higher, particularly cedrol.

BACKGROUND OF THE INVENTION

[0001] 1. Field of The Invention

[0002] The present invention relates to an autonomic nerve regulatingagent having sedative action, sleep improving action, stress mitigationaction, and the like.

[0003] 2. Discussion of The Related Art

[0004] When the balance between the activities of the parasympatheticnervous system and the sympathetic nervous system is upset by physicaland mental stress, the resulting disequilibrium in the autonomic nervoussystem can lead to mental aggravation, making it difficult to fallasleep very easily (sleep induction) and resulting in shallow sleep. Itis believed that stimulating the physiological predominance of theparasympathetic activity over the sympathetic activity can reduce stressand calm aggravated mental states, thus inducing favorable sleep.

[0005] Methods that have long been used to thus stimulate thepredominance of the parasympathetic activity over the sympatheticactivity include the oral or percutaneous administration of activeingredients to humans, as well as aromatherapy involving vaporizablefragrance compositions to allow the vapors to be inhaled. Recentproposals include methods in which bitter orange essential oil (JapaneseLaid-Open Patent Application Kokai) H4-128234) and jasmine lactone(Japanese Laid-Open Patent Application (Kokai) H6-40911) areadministered by absorption via the nasal mucosa, oral mucosa, orpulmonary tissue for better sleep induction.

[0006] The use of the low-boiling components of cedar wood oil (such asα-pinene, α-cedrene, β-cedrene, and caryophyllene) as a sedativeessential oil has also been proposed (Japanese Laid-Open PatentApplication (Kokai) H5-255688).

[0007] It is not altogether clear-whether or-not the effects of suchfragrances or essential oil components are determined solely by theiraction on the autonomic nervous system, and it has been assumed thataction mediated by other physiological routes, including the lowercentral nervous system, may be involved.

[0008] There is substantial individual variation in the sensitivity toand preference for scents (fragrances) such as bitter orange essentialoil and jasmine lactone. While these may have sedative and sleepinducing action for some people, they may on the contrary bedisagreeable or irritating to others. There is thus a need for acomponent or method capable of universally improving autonomic nervousimbalances (in other words, restoring the balance to a physiologicallyideal state) whose effects are not biased by odor perceptions.

[0009] The low-boiling components of cedar wood oil have a stronglycharacteristic fragrance, and their sedative actions are also subject toconsiderable individual variation in terms of people's sensitivity andpreferences in the same manner as bitter orange essential oil and thelike.

SUMMARY OF THE INVENTION

[0010] An object of the present invention is to provide an autonomicnerve regulating agent, sleep improving agent, and agent for mitigatingstress (henceforth referred to as autonomic nerve regulating agents)which have a sedative action and the like for individuals whosesympathetic activity is predominant, irrespective of the variation inindividual sensitivity or preference for fragrances, and conversely haveaction in restoring the physiological balance to within normal range inindividuals whose parasympathetic activity is predominant.

[0011] The inventors have discovered that emotions (moods) can beeffected or modified by some compounds which belong to sesquiterpenealcohols. These compounds are substantially odorless, that is, having anodor below the detectable threshold (in other words, causing no noticeof preference). Nevertheless, they have sedative or sleep improvingaction on individuals whose sympathetic activity is predominant (saidaction stimulating the predominance of the parasympathetic activity overthe sympathetic activity). Also they conversely have action instimulating the predominance of the sympathetic activity over theparasympathetic activity to restore the physiological balance to withinnormal range in individuals whose parasympathetic activity ispredominant, and have an odor substantially below the detectablethreshold.

[0012] That is, the present invention provides an autonomic nerveregulating agent, a sleep improving agent, or a stress mitigating agent,comprising sesquiterpene alcohol with a boiling point of 250° C. orhigher with essentially no detectable odor. By having an odorsubstantially below the detectable threshold, the autonomic nerveregulating agents described herein can be administered to people withoutresulting in negative or adverse reactions to the odors and fragrancescommonly associated with aromatherapy.

[0013] Another object of the present invention is to provide avaporization system comprising a vaporization-promoting element and acomposition comprising a sesquiterpene alcohol having an odorsubstantially below the detectable threshold and with a boiling point of250° C. or higher.

[0014] The present invention also affords an autonomic nerve regulatingmethod, a sleep improving method, and a stress mitigation method.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 A through 1F illustrate the measurement results for thevarious test parameters of the autonomic nerve regulating agent inExample 1.

[0016]FIGS. 2A through 2F illustrate-the measurement results for thevarious test parameters of the autonomic nerve regulating agent inExample 2.

[0017]FIGS. 3A through 3D illustrate the measurement results for varioustest of the autonomic nerve regulating agent (sleep improving agent) inExample 3.

[0018]FIG. 4 illustrates a method for massaging the face.

[0019]FIGS. 5A through 5F illustrate the measurement results for thevarious test parameters of the autonomic nerve regulating agent(massaging agent) in Example 4.

[0020]FIG. 6 illustrates the measurement results for R—R interval in ECG(electrocardiogram) when using the vaporization system (mask) in Example5.

[0021]FIG. 7 illustrates the measurement results for Lsum/Hsum whenusing the vaporization system (mask) in Example 5.

[0022]FIG. 8 illustrates the measurement results for Hsum when using thevaporization system (mask) in Example 5.

[0023]FIGS. 9A through 9D illustrate the results of emotion spectrumanalysis when using the vaporization system (mask) in Example 5.

[0024]FIG. 10 illustrates the measurement results for sleepingefficiency when using the vaporization system (mask) in Example 6.

[0025]FIG. 11 illustrates the measurement results for intermittentawakening when using the vaporization system (mask) in Example 6.

[0026]FIG. 12 illustrates the measurement results for sleepingefficiency when using the cedrol-treated bedding in Example 7.

[0027]FIG. 13 illustrates the measurement results for intermittentawakening when using the cedrol-treated bedding in Example 7.

[0028]FIG. 14 illustrates the measurement results for R-R interval inECG with the licking of candy containing-cedrol in Example 8.

[0029]FIG. 15 illustrates the measurement results for Hsum with thelicking of candy containing cedrol in Example 8.

[0030]FIG. 16 illustrates the measurement results for Lsum/Hsum with thelicking of candy containing cedrol in Example 8.

[0031]FIGS. 17A through 17D illustrate the results of emotion spectrumanalysis with the licking of candy containing cedrol in Example 8.

[0032]FIG. 18 is a table of the measurement results for vapor pressureof cedrol.

[0033]FIG. 19 is a curve of the vapor pressure of cedrol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The autonomic nerve regulating agents of the present inventioncomprise a sesquiterpene alcohol with a boiling point of 250° C. orhigher at atmospheric pressure, as compounds which have sedative actionand sleep improving action for individuals whose sympathetic activity ispredominant, and which conversely have action in stimulating thesympathetic activity to predominance over the parasympathetic activityin individuals whose parasympathetic activity is predominant, as well asin improving emotions such as anger, stress, sense of joy or sadness,and relaxation (specifically, relieving stress and anger, enhancing asense of joy, mitigating sadness, and enhancing a sense of relaxation).At least part of the mechanism resulting in such action is attributed toreception via the primary olfactory nervous system and stimulation ofthe autonomic nervous system through the lower central nervous system,with the additional possibility that the higher central nervous systemis stimulated via the lower central nervous system.

[0035] As used in the present invention, “autonomic nervous regulation”indicates of disequilibrium in the autonomic nervous system within anonmorbid range, defined as at least one, preferably at least two, andeven more preferably at least three of the following phenomena (1)through (6), as determined in accordance with the following examples insubjects whose sympathetic activity is greater than usual:

[0036] (1) meaningful decrease of systolic blood pressure (SBP);

[0037] (2) meaningful decrease of diastolic blood pressure (DBP);

[0038] (3) meaningful extension of R—R interval in ECG;

[0039] (4) meaningful increase of Hsum in R—R interval fluctuations;

[0040] (5) meaningful decrease of Lsum/Hsum in R—R intervalfluctuations; and

[0041] (6) meaningful reduction of respiratory rate.

[0042] Examples of sesquiterpene alcohols with a boiling point of 250°C. or higher having action capable of inducing such phenomena includecedrol (boiling point 295° C.), cedrenol (boiling point 270° C.),farnesol (boiling point 263° C.), patchouli alcohol (boiling point 140°C./8 mmHg), eugenol (boiling point 254-255° C.), α-santalol (boilingpoint 302° C.), α-bisabolol (boiling point 265° C.), sclareol (boilingpoint 340° C. or higher), geranyl linalool (boiling point 340° C.),isophytol (boiling point 310° C. or higher), and nerolidol (boilingpoint 276° C.), as well as globulol and guaiol. Of these, sesquiterpenealcohols having an odor substantially below the detectable threshold,are preferred, while cedrol is particularly preferred because it affordsexcellent effects in the invention and is readily available. Cedrol oflow purity is considerably affected by other fragrance components and ishard to obtain in crystalline form with good handling properties. Thepurity is thus preferably at least 70%, more preferably at least 80%,even more preferably at least 90%, still more preferably at least 95%,and especially at least 97.0%.

[0043] “An odor substantially below the detectable threshold” means anodor that cannot be detected by at least 5, and preferably 8 or more,individuals among 10 Japanese individuals with normal olfactoryfunction.

[0044] The volatile, low boiling components thought to be responsiblefor the odors and fragrances associated with, for example, cedar woodoil, jasmine lactone and bitter orange essential oil are not present inthe autonomic nerve regulating agents described herein at concentrationsordinarily detectable by humans. Sesquiterpene alcohols that are free oflow boiling components are essentially odorless. These autonomic nerveregulating agents may include sesquiterpene alcohols having a boilingpoint of greater than 150° C., preferably greater than 200° C., and mostpreferably greater than 250° C.

[0045] The amount of the sesquiterpene alcohol with a boiling point of250° C. or higher (at atmospheric pressure) that is used in the presentinvention can be determined as desired according to the intendedapplication of the autonomic nerve regulating agents (such asmiscellaneous goods, including base cosmetics, make-up cosmetics, haircosmetics, bathing agents, poultices, massaging agents, indoorfragrances, and masks; food products and beverages, including functionalfood products; tooth paste or mouth washes; various fiber products,including seat covers, bedding, wall paper, furniture, and clothing) oraccording to the formulation that is used (such as solutions, solids,powders, sprays, gels, and pastes). When used as a lotion, for example,the amount is preferably 0.01 to 0.05 wt % in consideration of thedissolution stability of the sesquiterpene alcohol. When used as anemulsion or cream, the amount is preferably 0.01 to 7.50 wt % in theconsideration of the emulsion stability. When used in the form of abathing agent, the type of formulation and the amount may be selected soas to result in a concentration of at least 0.01 ppm, preferably 0.1 to1000 ppm, and even more preferably 5 to 1000 ppm, in the bath water.

[0046] Where in this application a range is provided all values andsubranges between the stated ranges are expressly included. For examplethe range 0.01 to 7.50% includes all between lying values including, forexample, 5, 2, 1, 0.5 and 0.05 etc. %.

[0047] Various additives commonly used in a variety of applications(such as oils, fillers, colorants, polymers, humectants, UV absorbents,pH adjusting agents, antioxidants, surfactants, and fragrances) can beblended as desired in the autonomic nerve regulating agents of thepresent invention according to the intended application and theformulation that is used.

[0048] The autonomic nerve regulating agents of the present inventioncan be administered to humans through respiration, the oral mucosa, thenasal mucosa, orally, transdermal penetration, or via the respiratorytract. Autonomic nerve regulating agents of the present invention, suchas orally administered tablets, need not necessarily contain thesesquiterpene alcohol in a vaporizable state. However, foradministration to a large, unspecified number of individuals, anextremely low concentration of sesquiterpene alcohol is preferablydispersed in the space and its vicinity where the administration takesplace, so as to allow it to be administered through the nasal mucosa orrespiratory tract through the natural respiration of the individuals.The autonomic nerve regulating agents of the present invention thuspreferably contain a sesquiterpene alcohol such as cedrol in avaporizable state. The vaporizable state means a state in which thematerial is dispersed in the form of vapor, minute solid particles, ordroplets into the air, either through natural vaporization or as aresult of treatment such as heating, ultrasonic irradiation, steamheating, or negative (or minus) ionization with a vaporization-promotingelement.

[0049] The method of using the autonomic nerve regulating agents of thepresent invention can also be determined as desired according to theintended application and the formulation that is used. For example, whenused in the form of a pad soaked with a sesquiterpene alcohol having aboiling point of 250° C. or higher, the pad may be heated by means ofheat generated by a vaporization-promoting element such as an electricheater to allow the sesquiterpene alcohol to be vaporized, or it can beheated by hot steam produced by a vaporization-promoting element such asthe mask described in Japanese Laid-Open Patent Application (Kokai)2000-42125, which comprises a water vapor-producing element, to allowthe sesquiterpene alcohol to be vaporized. When a sesquiterpene alcoholhaving a boiling point of 250° C. or higher is solubilized in aqueousmedia, liquid droplets containing the sesquiterpene alcohol can bevaporized through the application of ultrasonic waves from avaporization-promoting element such as an ultrasonic humidifier, or thesesquiterpene alcohol can be vaporized through negative ionization bymeans of a device for breaking up water which involves exploiting theLenard effect. In these cases, the sesquiterpene alcohol should bevaporized at a concentration of between 0.01 to 100 ppb in the air, astoo low a concentration will not afford the desired results, while toohigh a concentration will result in the condensation of fine particlesin the air.

[0050] The sesquiterpene alcohols in the present invention may also bevaporized naturally at ambient temperature without the aforementionedtreatment. That is, embodiments using sesquiterpene alcohol in avaporizable state are not limited to the use of a vaporization-promotingelement, and can also include simply spraying the autonomic nerveregulating agent containing sesquiterpene alcohol on bedding or wallpaper; so-called “leave on” types of cosmetics which are applied to theskin without being washed off; and compositions which are used by beingleft for a certain period of time in the mouth (such as tooth paste orcandy)

[0051] As noted above, through their action on the autonomic nervoussystem, the sesquiterpene alcohols in the present invention are capableof mitigating physical or mental stress and of soothing aggravatedmental states. Also they are capable of improving the quality of sleep,such as shortening the sleep latency (the time it takes an individual tofall asleep), reducing the number of intermittent awakening andshortening the time needed to wake up, improving sleep efficiency(=total sleep time/time in bed), enhancing the good feeling upon waking,and prolonging the period of deep sleep (non-REM sleep). The presentinvention is thus suitable for use as a sleep improving agent.

[0052] As used in the present invention, “sleep improvement” indicatesthe qualitative or quantitative improvement of sleep within thenonmorbid range, defined as at least one, preferably at least two, andmore preferably three or more of the following (1) through (4), asdetermined in accordance with the following examples in subjects whosuffer from poor sleep:

[0053] (1) meaningful shortening of sleep latency;

[0054] (2) meaningful reduction of number of intermittent awakening;

[0055] (3) meaningful increase of sleeping efficiency; and

[0056] (4) meaningful improvement in terms of tension and fatigue basedon POMS.

[0057] The sesquiterpene alcohols of the present invention also have aneffect on the expression of emotions (moods) and the state thereof,which is influenced by the higher central nervous system governingpreferences. Specifically, they allow composure to be recovered,anger/stress or sadness to be controlled, and a sense of joy andrelaxation to be enhanced. The present invention is thus suitable foruse to relieve stress.

[0058] Such changes of emotion can be determined by emotion spectrumanalysis based on brain waves (T. Mushy et al., “Emotion spectrumanalysis method (ESAM) for monitoring the effects of art therapy appliedon demented patients,” Cyber Psychology & Behavior, 3, 441-446 (2000),the relevant portions thereof which describe emotion spectrum analysisare incorporated herein by reference).

[0059] As used in the present invention, “stress mitigation” indicatesthat mental or physical stress is mitigated within the nonmorbid range,defined as improvement in at least one, preferably at least two, andmore preferably three or more of the parameters of “anger/stress,”“joy,” “sadness,” and “relaxation” by emotion spectrum analysis asdetermined in accordance with the following examples for subjectsexperiencing stress.

[0060] By providing effects such as sleep improvement and stressmitigation, the present invention can also improve menopause, PMS(premenstrual syndrome), physical vitality and appetite.

[0061] The use of a compound with odor substantially below thedetectable threshold, particularly cedrol, from among the sesquiterpenealcohols employed in the present invention allows the autonomic nerveregulating agents of the present invention to produce the aforementionedeffects in individuals or an unspecified number of individuals,regardless of their disposition towards fragrances. The autonomic nerveregulating agents of the present invention can accordingly be used notonly in private spaces such as bedrooms and bathrooms, but also inpublic spaces such as meeting rooms, private rooms, airplanes, vehicles,hotels, nursing facilities, hospitals, nursing homes, public healthfacilities, department stores, airports, libraries, stations, andbusiness offices, in any configuration or at any period of time (such asmorning, afternoon, evening, before bed, after bed, during work, orduring exercise) or for any physical condition (such as during fatigue,good health, or stress).

[0062] A sesquiterpene alcohol with a boiling point of 250° C. or highercan be directly vaporized as needed by a vaporization system comprisingthe aforementioned vaporization-promoting element and a composition suchas an autonomic nerve regulating agent, stress mitigating agent, andsleep improving agent comprising a sesquiterpene alcohol with a boilingpoint of 250° C. or higher in a vaporizable state as needed combinedwith a desired carrier or medium.

[0063] It is not necessary to operate the vaporization-promoting elementthroughout the entire sleeping period in order to achieve the sleepimproving effects, for example. Satisfactory effects will be achievedwith shorter periods of time, such as about 30 minutes to 2 hours ofoperation, before going to bed and a short time after falling asleep.

[0064] This application is based on and claims benefit of priority toInternational Application PCT/JP01/00928 filed on Feb. 9, 2001 andJapanese priority document JP 2000-38260 filed on Feb. 10, 2000, each ofwhich is incorporated by reference in its entirety.

EXAMPLES

[0065] The present invention is illustrated in further detail in thefollowing examples. Reference Example 1

[0066] The vapor pressure of purified cedrol (molecular weight 222g•mol⁻¹) used in the following examples was determined by a staticmethod and a gas flow method (temperature: 22, 50, and 75° C. forsolids; 100 and 125° C. for liquids).

[0067] In the static method, samples were taken from hermetically sealedcontainers, a constant temperature was established, and the equilibriumvapor pressure at that temperature was directly measured using apressure gauge (OECD Test Guidelines 104: Static Measurement of VaporPressure).

[0068] In the gas flow method, carrier gas (nitrogen gas) was allowed toflow so as to come into contact with a solid or liquid sample at acertain temperature to saturate the sample vapor, and the vapor density(vaporization quantity/volume) was measured so as to determine the vaporpressure hypothetically in accordance with ideal gas principles. Thevapor density herein referred to is calculated from the samplevaporization rate (rate of loss) determined using an electrical balance,and the carrier gas flow rate determined using a flow rate gauge.However, since the sample vapor saturation is usually incomplete, thevapor density level is dependent on flow rate, so the vapor density wasmeasured at varying flow rates for extrapolation to a zero flow rate todetermine the saturated vapor density. The following formula was used todetermine the vapor pressure from the vapor density,

P=(k/v)Vπ/M

[0069] (where P is the vapor pressure (mmHg), k is the vaporization rate(mg/min), v is the carrier gas flow rate (ml/min), k/v is the vapordensity (mg/ml.), V is the carrier gas molar volume (L/mol), π is thesystem pressure (mmHg), and M is the sample molecular weight; 1mmHg=1.33×10² Pa).

[0070] The results are given in FIG. 18, and are plotted on a graph(FIG. 19).

[0071] The results show that cedrol can be vaporized at ambienttemperature (unheated).

Example 1

[0072] The subjects were ten women in their twenties complaining offatigue (sympathetic overactivity), who were asked to inhale, for 30seconds, cedrol dissolved in dipropylene glycol (10 wt % concentration),while ECG at rest (chest V5 lead), blood pressure (tonometry), andrespiration (pulmonary volume instantaneously measured by respiratoryrate sensor) were monitored. The changes in parameters before and aftermeasurement were compared. Frequency analysis of R—R intervalfluctuations was performed for low frequency components integratingamplitudes 0.02 to 0.12 Hz (sum of low frequency: Lsum) and highfrequency components integrating amplitudes 0.12 to 2.00 Hz (sum of highfrequency: Hsum) using the rapid Fourier transform. As used here, theHsum is an indicator of parasympathetic nervous activity, and theLsum/Hsum is an indicator of sympathetic nervous activity.

[0073] The measurement results were statistically analyzed by Welch'st-test or Student's t-test based on the F test.

[0074] Results

[0075] 1) The systolic blood pressure (SBP) was meaningfully lower (5%)after inhalation compared to before inhalation (FIG. 1A).

[0076] 2) The diastolic blood pressure (DBP) was meaningfully lower (5%)after inhalation compared to before inhalation (FIG. 1B).

[0077] 3) The ECG R—R interval was meaningfully longer (5%) afterinhalation compared to before inhalation (FIG. 1C).

[0078] 4) The Hsum was meaningfully greater (5%) after inhalationcompared to before inhalation (FIG. 1D).

[0079] 5) The Lsum/Hsum was meaningfully lower (5%) after inhalationcompared to before inhalation (FIG. 1E).

[0080] 6) The respiratory gate (RR) was meaningfully lower (5%) afterinhalation compared to before inhalation (FIG. 1F).

[0081] Conclusions

[0082] The above results demonstrate that the inhalation of cedrol bythe subjects resulted in sedative effects in various parts of the body,suppressed sympathetic overactivity, and resulted in the predominance ofthe parasympathetic activity.

Example 2

[0083] The subjects were ten insomniac women in their twenties (underconsiderable pressure to get to sleep, with parasympathetic predominanceto excess), who were asked to inhale, for 30 seconds, cedrol dissolvedin dipropylene glycol (10 wt % concentration), while ECG at rest (chestV5 lead), blood pressure (tonometry), and respiration (pulmonary volumeinstantaneously measured by respiratory rate sensor), and skin bloodflow of forehead (measured by laser Doppler methods) were monitored. Thechanges in parameters before and after measurement were compared.Frequency analysis of R—R interval fluctuations and statistical analysisof the measurement results were done in the same manner as in Example 1.

[0084] Results

[0085] 1) The systolic blood pressure (SBP) was meaningfully higher (5%)(within physiologically normal range) after inhalation compared tobefore inhalation (FIG. 2A).

[0086] 2) The diastolic blood pressure (DBP) was meaningfully higher(5%) (within physiologically normal range) after inhalation compared tobefore inhalation (FIG. 2B).

[0087] 3) There was no meaningful change in ECG R—R interval afterinhalation compared to before inhalation (FIG. 2C).

[0088] 4) The Hsum tended to be lower (5%) inhalation compared to beforeinhalation (FIG. 2D).

[0089] 5) The Lsum/Hsum tended to be higher after inhalation compared tobefore inhalation (FIG. 2E).

[0090] 6) There was no meaningful difference in respiratory rate (RR)after inhalation compared to before inhalation (FIG. 2F).

[0091] Conclusion

[0092] The above results demonstrate that the inhalation of cedrol bythe subjects resulted in a return to a state of equilibrium in variousparts of the body, and suppressed parasympathetic overactivity whilesimultaneously elevating the sympathetic underactivity, therebyresulting in a suitable autonomic nervous balance.

Example 3

[0093] The subjects were ten women in their twenties suffering from poorsleep. ECG (chest V5 lead), brain waves (C3, O1 in the international10-20 method), respiration (impedance method: abdomen and chest),superficial electromyogram (bipolar lead of left and right mentalismuscles), and ocular movement (bipolar lead without horizontally linkingleft and right eye-sockets) were monitored from the time the subjectswent to bed until they woke in a 40 m² room. The cedrol was administeredby placing Petri dishes filled with cedrol on 95° C. hot plates so thatapproximately 100 mg was vaporized per hour (about 1 ppb/hr), from thetime subjects went to bed until they woke. Measurements were taken for 7days. No administration took place on the first two days, in order toallow subjects to become acclimated to the measuring instruments andenvironment (control). On the third day, administration was managedwithout anything placed on the hot plates (placebo). After 3 days,cedrol was administered on the 7th day.

[0094] The subjects were interviewed about their condition on wakingusing a questionnaire based on POMS (profile of mood states) to assessmood. The changes in the parameters measured during the administrationof cedrol and placebo treatment were compared. Awakening and sleepstages were determined in accordance with international standards fordetermining sleep stages (Sleep Brain Wave Atlas, pp. 3-9, IshiyakuShuppan KK, published September, 1971, the relevant portions thereofwhich describe sleep analysis and standards are incorporated herein byreference). Frequency analysis of R—R interval fluctuations andstatistical analysis of the measurement results were done in the samemanner as in Example 1.

[0095] Results

[0096] 1) Hsum was meaningfully increased (5%) during non-REM sleep whencedrol was administered compared to the placebo treatment (FIG. 3A).

[0097] 2) The cumulative incidence of stages 3 and 4 of sleep wasmeaningfully greater (5%) when cedrol was administered compared to theplacebo treatment (FIG. 3B).

[0098] 3) The respiratory rate (RR) was meaningfully lower (5%) duringnor-REM sleep when cedrol was administered compared to the placebotreatment (FIG. 3C).

[0099] 4) POMS revealed meaningful (5%) improvement in tension andfatigue when cedrol was administered on the 7th day compared to beforeadministration and the 3rd day (placebo treatment) (FIG. 3D).

[0100] Conclusion

[0101] The above results reveal that subjects who slept while inhalingthe fumes of cedrol (100 mg/hr) had a meaningfully deeper sleep, alonger non-REM sleep cycle, and a better quality of sleep, indicating ashift to parasympathetic predominance.

Example 4

[0102] The subjects were ten women in their twenties experiencingfatigue (sympathetic overactivity), who were asked to massage theirfaces as shown in FIG. 1 of Japanese Laid-Open Patent Application(Kokai) H10-113369 using the massage cream preparation in Table 1 once aday before sleep for 4 continuous weeks; Specifically, as shown in FIG.4, (step 1) approximately 2 mL massage cream was spread on the hands andapplied to the face, (step 2) the face was massaged 2 to 3 times withall four fingers (index to pinky) of both hands in a line from thecorners of the mouth to the wings of the nose (direction (a) in FIG. 4),(step 3) the face was massaged 2 to 3 times in circles outward from thecanter of the cheeks (direction (b) in FIG. 4), (step 4) the face wasmassaged 2 to 3 times in arcs outward from the center of the forehead(direction (c) FIG. 4), (step 5) steps 2 through 4 were repeated 3times, and (step 6) the face under the eyes was massaged 3 times in arcsgradually extending outward (direction (d) in FIG. 4).

[0103] The ECG at rest (chest V5 lead), blood pressure (tonometry), andrespiration (pulmonary volume instantaneously measured by respiratoryrate sensor) were monitored in the morning before and 4 weeks after thebeginning of massaging, so as to compare changes in the parameters.Frequency analysis of R—R interval fluctuations and statistical analysisof the measurement results were done in the same manner as in Example 1.TABLE 1 Components Wt % Oil components: beeswax 6.0 cetanol 5.0 reducedlanolin 8.0 squalene 37.5 fatty acid glycerin 4.0 Emulsifiers:oleophilic glycerin monostearate 2.0 polyoxyethylene (20 EO) sorbitanlaurate ester 2.0 Aqueous phase: propylene glycol 5.0 purified water30.0 cedrol 0.5 preservative/antioxidant proper amount

[0104] Results

[0105] 1) The systolic blood pressure (SBP) was meaningfully lower (5%)4 weeks after the beginning of massaging compared to before massaging(FIG. 5A).

[0106] 2) The diastolic blood pressure (DBP) was meaningfully lower (5%)4 weeks after the beginning of massaging compared to before massaging(FIG. 5B).

[0107] 3) The ECG R—R interval was meaningfully longer (5%) 4 weeksafter the beginning of massaging compared to before massaging (FIG. 5C).

[0108] 4) The Hsum was meaningfully higher 4 weeks after the beginningof massaging compared to before massaging (FIG. 5D).

[0109] 5) The Lsum/Hsum was meaningfully lower 4 weeks after thebeginning of massaging compared to before massaging (FIG. 5E).

[0110] The respiratory rate (RR) was meaningfully lower (5%) 4 weeksafter the beginning of massaging compared to before massaging (FIG. 5F).

[0111] Conclusion

[0112] The above results reveal that massaging the face using massagecream containing a cedrol blend once a day for 4 continuous weeksresulted in sedative effects in various parts of the body, thesuppression of sympathetic overactivity, and a shift to parasympatheticpredominance.

Example 5

[0113] The subjects were twenty women in their twenties experiencingmental and physical stress, who were asked to wear the following masksa) through d) (vaporization systems) around the mouth and nose at atemperature of 25° C. and a humidity of 50%;

[0114] (mask a) mask incorporating a heating element (mask surfacetemperature about 70° C.) (mask described in Example 3 of JapaneseLaid-Open Patent Application (Kokai) 2000-42125);

[0115] (mask b)) mask comprising a support (filter paper) impregnated onthe surface with a prescribed amount of cedrol (2.5×10⁻³ g) and a maskincorporating a heating element (mask surface temperature about 70° C.)(mask described in Example 3 of Japanese Laid-Open Patent Application(Kokai) 2000-42125) the support being attached to the surface of theheating element;

[0116] (mask c)) mask incorporating a hot steam generating element (masksurface temperature about 70° C.; steam rate 0.5 g/min) (mask describedin Example 1 of Japanese Laid-Open Patent Application (Kokai)2000-42125); and

[0117] (mask d)) mask comprising a support (filter paper) impregnated onthe surface with a prescribed amount, of cedrol (2.5×10⁻³ g) and a maskincorporating a hot steam generating element (mask surface temperatureabout 70° C.; steam rate 0.5 g/min) (mask described in Example 1 ofJapanese Laid-Open Patent Application (Kokai) 2000-42125), the supportbeing attached to the surface of the hot steam generating element.

[0118] ECG (chest V5 lead) and emotion spectrum analysis based on brainwaves (T. Musha et al, ibid.) were performed for 3 minutes from 17 to 20minutes after the masks had been applied. Frequency analysis of R—Rinterval fluctuations was performed for low frequency componentsintegrating amplitudes 0.02 to 0.12 Hz (sum of low frequency: Lsum) andhigh frequency components integrating amplitudes 0.12 to 2.00 Hz (sum ofhigh frequency: Hsum) using the rapid Fourier transform, as well asLsum/Hsum.

[0119] The measurement results were statistically analyzed by multiplecomparative analysis of variance.

[0120] Results

[0121] (1) The ECG R—R integral was meaningfully longer with the mask d)(hot steam+cedrol treatment) than with the other masks [mask d) p<0.01](FIG. 6).

[0122] (2) The Hsum was meaningfully greater with the mask d) (hotsteam+cedrol treatment) than with the other masks [mask d) p<0.05; othermasks p<0.01] (FIG. 7).

[0123] (3) The Lsum/Hsum was meaningfully lower with the mask d) (hotsteam+cedrol treatment) than with the other masks [mask d) p<0.05; othermasks p<0.01] (FIG. 8).

[0124] (4) the emotional spectrum was meaningfully improved in terms ofanger/stress (FIG. 9A), joy (FIG. 9B), sadness (FIG. 9C), and relaxation(FIG. 9D) with the mask d) (hot steam+cedrol treatment.) than with theother masks [mask d) p<0.05: other masks p<0.01].

[0125] Conclusion

[0126] The above results demonstrate that the effects achieved throughthe inhalation of cedrol contained in the mask resulted in bettercalmness and tranquillity (relaxation effects) when used with hot steamthan with heat. The effects appear to be peripheral effects in thevarious body parts as well as effects on the conscious level.

Example 6

[0127] The subjects were twenty women in their twenties experiencingmental and physical stress, who were asked to wear the following masksa) through d) (vaporization systems) around the mouth and nose at atemperature of 23° C. and a humidity of 50% while resting in a seatedposition for 30minutes:

[0128] (mask a)) mask incorporating a heating element (mask surfacetemperature about 70° C.) (mask described in Example 3 of JapaneseLaid-Open Patent Application (Kokai) 2000-42125):

[0129] (mask b)) mask comprising a support (filter paper) impregnated onthe surface with a prescribed amount of cedrol (2.5×10⁻³ g) and a maskincorporating a heating element (mask surface temperature about 70° C.)(mask described in Example 3 of Japanese laid-Open Patent Application(Kokai) 2000-42125), the support being attached to the surface of theheating element;

[0130] (mask c)) mask incorporating a hot steam generating element (masksurface temperature about 70° C.; steam rate 0.5 g/min) (mask describedin Example 1 of Japanese Laid-Open Patent Application (Kokai)2000-42125); and

[0131] (mask d)) mask comprising a support (filter paper) impregnated onthe surface with a prescribed amount of cedral (2.5×10 ⁻³ g) and a maskincorporating a hot steam generating element (mask surface temperatureabout 70° C.; steam rate 0.5 g/min) (mask described in example 1 ofJapanese Laid-Open Patent Application (Kokai) 2000-42125), the supportbeing attached to the surface of the hot steam generating element. Themasks were then removed, the subjects were asked to lie down, and thesleeping efficiency and intermittent awakening were assessed usingactigrams while the subjects slept until the following day.

[0132] Statistical analysis of the measurement results was the same asin Example 5.

[0133] Results

[0134] (1) Sleeping efficiency was meaningfully better with mask d) (hotsteam+cedrol treatment) than with the other masks [mask-d) p<−0.05;other masks p<0.01] (FIG.10).

[0135] (2) There were meaningfully fewer intermittent awakening withmask d) (hot steam+cedrol treatment) than with the other masks [mask d)p<0.05; other mask p 0.01 ] (FIG. 11).

[0136] Conclusion

[0137] The results demonstrate that the effects achieved through theinhalation of Cedrol contained in the mask resulted in better sleepingefficiency when used with hot steam than with heat.

Example 7

[0138] The subjects were twenty insomniac women in their fifties, whilesleep was assessed from 3 hours before bed until wakening for 4 weeks ina room (sleeping room) at a temperature of 23° C. and a humidity of 50%.The first week served as a control. For the last 3 weeks, the test wasconducted by replacing the curtains, wall paper, flooring, pillows,sheets, and bedding with those which had been coated with cedral (1.5μg/cm²).

[0139] The subjects ware actigrams for 4 continuous weeks on theopposite of their leading arm to allow assessment of the sleepingefficiency and intermittent awakening. Analyzed data for the cedrolcoatings were from the 15th to 21st days following application.

[0140] Statistical analysis of the measurement results was the same asin Example 5.

[0141] Results

[0142] (1) Sleeping efficiency was meaningfully better with cedroltreatment than during the control (p<0.01) (FIG. 12).

[0143] (2) There were meaningfully fewer intermittent awakening withcedrol treatment than during the control (p<0.01)(FIG. 13).

[0144] Conclusion

[0145] The results demonstrate that sleeping in a room using fiberproducts, furnishings, and bedding coated with cedrol resulted in farbetter sleep than when sleeping in a room using fiber products,furnishings, and bedding not coated with cedrol.

Example 8

[0146] The subjects were twenty women in their twenties experiencingmental and physical stress, who were acclimated for 20 minutes to atemperature of 25° C. and humidity of 50% as a control. ECG (chest V5lead) and emotion spectrum analysis based on brain waves were conducted20 minutes after the subjects licked one candy of 5 g containing nocedrol (58.0 wt % granulated sugar, 17.0 wt % water, 25 wt % starchsyrup, and a suitable amount of coloring), or another candy of 5 gcontaining 0.01 wt % cedrol (58.0 wt % granulated sugar, 17.0 wt %water, 24.99 wt % starch syrup, 0.01 wt % cedrol, and a suitable amountof coloring),

[0147] Frequency analysis of the R—R interval fluctuations andstatistical analysis of the measurement results were the same as inExample 5.

[0148] Results

[0149] (1) The ECG R—R interval was meaningfully longer (p<0.01) whenthe subjects licked the candy containing cedrol than during the control,and was also meaningfully longer (p<0.01) than when the candy containingno cedrol was licked (FIG. 14).

[0150] (2) The Hsum was meaningfully greater (p<0.01) when the subjectslicked the candy containing cedrol than during the control, and was alsomeaningfully greater (p<0.01) than when the candy containing no cedrolwas licked (FIG. 1b).

[0151] (3) The Lsum/Hsum was meaningfully lower (p<0.01) when thesubjects licked the candy containing cedrol than during the control, andwas also meaningfully lower (p<0.01) than when the candy containing nocedrol was licked (FIG. 16).

[0152] (4) The emotion spectrum was meaningfully improved (p<0.01) interms anger/stress (FIG. 17A), joy (FIG. 17B), sadness (FIG. 17C), andrelaxation (FIG. 17D) when the subjects licked the candy containingcedrol than during the control, and was also meaningfully improved(p<0.01) than when the candy containing no cedrol was licked.

[0153] Conclusion

[0154] The above results demonstrate that, the effects of the candycontaining cedrol resulted in better calmness and tranquillity(relaxation effects) than the candy containing no cedrol. The effectsappear to be peripheral effects in the various body parts as well aseffects on the conscious level.

INDUSTRIAL APPLICABILITY

[0155] The autonomic nerve regulating agents of the present inventioncomprise a sesquiterpene alcohol with a boiling point of 250° C. orhigher (at atmospheric pressure), and act on individuals without anynoticeable perception of odor. Typical action includes bringing aboutthe relative predominance of the parasympathetic activity over thesympathetic activity in individuals with sympathetic overactivity (thatis, sympathetic suppression and/or parasympathetic stimulation), as wellas bringing about the relative predominance of the sympathetic activityover the parasympathetic activity in individuals with parasympatheticoveractivity. The invention can thus control the balance between theparasympathetic and sympathetic activities, regardless of individualsensitivity to or preference for fragrances, can normalize autonomicnerve disequilibrium, and has favorable effects on individuals such assedative, sleep improving, and stress mitigating effects.

1. A method for regulating autonomic nerve activity in a person in needthereof, comprising administering a composition comprising asesquiterpene alcohol to said person in an amount effective forregulating autonomic nerve activity, wherein said sesquiterpene alcoholhas a boiling point of at least 250° C. and said composition has an odorbelow a detectable threshold.
 2. The method for regulating autonomicnerve activity claimed in claim 1, wherein said autonomic nerveregulated activity is at least one activity selected from the groupconsisting of sleep, stress, parasympathetic activity, sympatheticactivity and mood.
 3. The method claimed in claim 1, wherein thesesquiterpene alcohol is selected from the group consisting of cedrol,cedrenol, farnesol, patchouli alcohol, eugenol, α-santalol, α-bisabolol,β-caryophyllene alcohol, vetiverol, sclareol, geranyl linalool,isophytol, nerolidol, globulol and guaiol.
 4. The method claimed inclaim 1, wherein the sesquiterpene alcohol is cedrol.
 5. The methodclaimed in claim 4, wherein the cedrol is at least 97% pure.
 6. Themethod claimed in claim 1, wherein the sesquiterpene alcohol is in avaporizable state.
 7. The method claimed in claim 1, wherein thesesquiterpene alcohol is administered by inhalation.
 8. The methodclaimed in claim 7, wherein the sesquiterpene alcohol is present in airat a concentration of from 0.01 to 100 ppb.
 9. The method claimed inclaim 1, wherein the composition is administered orally.
 10. The methodclaimed in claim 1, wherein composition is administered transdermally.11. The method claimed in claim 10, wherein the composition isadministered by bathing in a mixture comprising water and thecomposition, and further wherein the sesquiterpene alcohol is present ata concentration of from to 5 to 1000 ppm in said mixture.
 12. The methodclaimed in claim 1, wherein the composition is administered by sprayingonto a bedding or a wall covering.
 13. The method claimed in claim 1,wherein the composition is administered to a plurality of persons bydispersing said composition in a space and further wherein thesesquiterpene alcohol is in a vaporizable state.
 14. The method claimedin claim 1, wherein the composition is administered by wearing a mask,wherein said mask comprises a heating element, a hot steam generatingelement and the sesquiterpene alcohol.
 15. A composition consistingessentially of a sesquiterpene alcohol in air, wherein saidsesquiterpene alcohol is present at a concentration of from 0.01 to 100ppb, and further wherein said sesquiterpene alcohol has an odor below adetectable threshold, a boiling point of at least 250° C. and is in avaporizable state.
 16. A lotion consisting essentially of ansesquiterpene alcohol, wherein said sesquiterpene alcohol is present ata concentration of from 0.01 to 0.05 weight percent, has an odor below adetectable threshold and has a boiling point of at least 250° C.
 17. Anemulsion consisting essentially of an sesquiterpene alcohol, whereinsaid sesquiterpene alcohol is present at a concentration of from 0.01 to7.50 weight percent, has an odor below a detectable threshold and has aboiling point of at least 250° C., and a carrier.
 18. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier orexcipient and composition, said composition comprising a sesquiterpenealcohol, wherein said composition has an odor below a detectablethreshold and said sesquiterpene alcohol has a boiling point of at least250° C.
 19. The pharmaceutical composition claimed in claim 18, furthercomprising an emulsifier, oil, glycol, sugar, starch or mixture thereof.20. A vaporization system comprising a vaporization promoting elementselected from the group consisting of a heat generating source, hotsteam, ultrasonic waves, negative ions, and combinations thereof, acarrier, and a sesquiterpene alcohol with an odor below a detectablethreshold and a boiling point of at least 250° C.